Method and apparatus for characterizing materials by using a mechanical resonator

ABSTRACT

A method and apparatus for measuring properties of a liquid composition includes a mechanical resonator, such as a cantilever, connected to a measurement circuit. The mechanical resonator can be covered with a coating to impart additional special detection propertied to the resonator, and multiple resonators can be attached together as a single sensor to obtain multiple frequency responses. The invention is particularly suitable for combinatorial chemistry applications, which require rapid analysis of chemical properties for screening.

FIELD OF THE INVENTION

[0001] The present invention generally relates to methods and apparatusfor rapidly screening an array of diverse materials that have beencreated at known locations on a single substrate surface. Morespecifically, the invention is directed to the use of ultrasonic and/ormechanical transducers to image and/or evaluate the individual elementsof a library of materials. The present invention is also directed tousing mechanical oscillators for measuring various properties of fluids(including both liquids and vapors), and more particularly to a methodand system using a mechanical oscillator (resonator) for measuringphysical, electrical and/or chemical properties of a fluid based on theresonator's response in the fluid to a variable frequency input signal.

BACKGROUND OF THE INVENTION

[0002] The discovery of new materials with novel chemical and physicalproperties often leads to the development of new and usefultechnologies. Currently, there is a tremendous amount of activity in thediscovery and optimization of materials, such as superconductors,zeolites, magnetic materials, phosphors, catalysts, thermoelectricmaterials, high and low dielectric materials and the like.Unfortunately, even though the chemistry of extended solids has beenextensively explored, few general principles have emerged that allow oneto predict with certainty the composition, structure and reactionpathways for the synthesis of such solid state compounds.

[0003] The preparation of new materials with novel chemical and physicalproperties is at best happenstance with our current level ofunderstanding. Consequently, the discovery of new materials dependslargely on the ability to synthesize and analyze new compounds. Givenapproximately 100 elements in the periodic table that can be used tomake compositions consisting of two or more elements, an incrediblylarge number of possible new compounds remains largely unexplored. Assuch, there exists a need in the art for a more efficient, economicaland systematic approach for the synthesis of novel materials and for thescreening of such materials for useful properties. Thus, any system thatcan analyze each compound's properties quickly and accurately is highlydesirable. Further, such a system would be useful in any applicationrequiring quick, accurate measurement of a liquid's properties, such asin-line measurement of additive concentrations in gasoline flowingthrough a conduit or detection of environmentally-offending molecules,such as hydrogen sulfide, flowing through a smokestack.

[0004] One of the processes whereby nature produces molecules havingnovel functions involves the generation of large collections (libraries)of molecules and the systematic screening of those collections formolecules having a desired property. An example of such a process is thehumoral immune system which in a matter of weeks sorts through some 10¹²antibody molecules to find one which specifically binds a foreignpathogen (Nisonoffet al., The Antibody Molecule (Academic Press, N.Y.,1975)). This notion of generating and screening large libraries ofmolecules has recently been applied to the drug discovery process.

[0005] Applying this logic, methods have been developed for thesynthesis and screening of large libraries (up to 10¹⁴ molecules) ofpeptides, oligonucleotides and other small molecules. Geysen et al., forexample, have developed a method wherein peptide syntheses are carriedout in parallel on several rods or pins (J. Immun. Meth. 102:259-274(1987), incorporated herein by reference for all purposes). Generally,the Geysen et al. method involves functionalizing the termini ofpolymeric rods and sequentially immersing the termini in solutions ofindividual amino acids. In addition to the Geysen et al. method,techniques have recently been introduced for synthesizing large arraysof different peptides and other polymers on solid surfaces. Pirrung etal have developed a technique for generating arrays of peptides andother molecules using, for example, light-directed,spatially-addressable synthesis techniques (U.S. Pat. No. 5,143,854 andPCT Publication No. WO 90/15070, incorporated herein by reference forall purposes). In addition, Fodor et al. have developed a method ofgathering fluorescence intensity data, various photosensitive protectinggroups, masking techniques, and automated techniques for performinglight-directed, spatially-addressable synthesis techniques (Fodor etal., PCT Publication No. WO 92/10092, the teachings of which areincorporated herein by reference for all purposes).

[0006] Using these various methods, arrays containing thousands ormillions of different elements can be formed (U.S. patent applicationSer. No. 08/805,727, filed Dec. 6, 1991, the complete disclosure ofwhich is incorporated herein by reference for all purposes). As a resultof their relationship to semiconductor fabrication techniques, thesemethods have come to be referred to as “Very Large Scale ImmobilizedPolymer Synthesis,” or “VLSIPS.TM.” technology. Such techniques have metwith substantial success in screening various ligands such as peptidesand oligonucleotides to determine their relative binding affinity to areceptor such as an antibody.

[0007] The solid phase synthesis techniques currently being used toprepare such libraries involve the sequential coupling of buildingblocks to form the compounds of interest. For example, in the Pirrung etal. method polypeptide arrays are synthesized on a substrate byattaching photoremovable groups to the surface of the substrate,exposing selected regions of the substrate to light to activate thoseregions, attaching an amino acid monomer with a photoremovable group tothe activated region, and repeating the steps of activation andattachment until polypeptides of the desired length and sequence aresynthesized. These solid phase synthesis techniques cannot readily beused to prepare many inorganic and organic compounds.

[0008] In PCT WO 96/11878, the complete disclosure of which isincorporated herein by reference, methods and apparatus are disclosedfor preparing a substrate with an array of diverse materials depositedin predefined regions. Some of the methods of deposition disclosed inPCT WO 96/11878 include sputtering, ablation, evaporation, and liquiddispensing systems. Using the disclosed methodology, many classes ofmaterials can be generated combinatorially including inorganics,intermetallics, metal alloys, and ceramics.

[0009] In general, combinatorial chemistry refers to the approach ofcreating vast numbers of compounds by reacting a set of startingchemicals in all possible combinations. Since its introduction into thepharmaceutical industry in the late 80's, it has dramatically sped upthe drug discovery process and is now becoming a standard practice inthe industry (Chem. Eng. News Feb. 12, 1996). More recently,combinatorial techniques have been successfully applied to the synthesisof inorganic materials (G. Briceno et al., SCIENCE 270, 273-275, 1995and X. D. Xiang et al., SCIENCE 268, 1738-1740, 1995). By use of varioussurface deposition techniques, masking strategies, and processingconditions, it is now possible to generate hundreds to thousands ofmaterials of distinct compositions per square inch. These materialsinclude high T_(c) superconductors, magnetoresistors, and phosphors.Discovery of heterogeneous catalysts will no doubt be accelerated by theintroduction of such combinatorial approaches.

[0010] A major difficulty with these processes is the lack of fast andreliable testing methods for rapid screening and optimization of thematerials. Recently, a parallel screening method based on reaction heatformation has been reported (F. C. Moates et al., Ind. Eng. Chem. Res.35, 4801-4803, 1996). For oxidation of hydrogen over a metallic surface,it is possible to obtain IR radiation images of an array of catalysts.The hot spots in the image correspond to active catalysts and can beresolved by an infrared camera.

[0011] Screening large arrays of materials in combinatorial librariescreates a number of challenges for existing analytical techniques. Forexample, traditionally, a heterogeneous catalyst is characterized by theuse of a micro-reactor that contains a few grams of porous-supportedcatalysts. Unfortunately, the traditional method cannot be used toscreen a catalyst library generated with combinatorial methods. First, aheterogeneous catalyst library synthesized by a combinatorial chemistrymethod may contain from a few hundred to many thousands of catalysts. Itis impractical to synthesize a few grams of each catalyst in acombinatorial format. Second, the response time of micro-reactors istypically on the order of a few minutes. The time it takes to reachequilibrium conditions is even longer. It is difficult to achievehigh-throughput screening with such long response times.

[0012] Another challenge with screening catalyst arrays is the lowconcentration of components that may be present in the reactions. Forexample, oxidation of ethylene to ethylene oxide can be carried out overa silver-based catalyst (S. Rebsdat et al., U.S. Pat. Nos. 4,471,071 and4,808,738). For a surface-supported catalyst with an area of 1 mm by 1mm and the same activity as the industrial catalyst, only about 10 partsper billion (ppb) of ethylene are converted into the desired ethyleneoxide when the contact time is one second.

[0013] Detection of such low component levels in the presence of severalatmospheres of reaction mixture is a challenge to analytical methods.Many analytical techniques, including optical methods such as four-wavemixing spectroscopy and cavity ring-down absorption spectroscopy as wellas conventional methods such as GC/MS, are excluded because of poorsensitivities, non-universal detectability, and/or slow response.Therefore an apparatus and methodology for screening a substrate havingan array of materials that differ slightly in chemical composition,concentration, stoichiometry, and/or thickness is desirable.

[0014] It is therefore an object of the invention to measuresimultaneously both the physical and the electrical properties of afluid composition using a mechanical resonator device.

[0015] It is also an object of the invention to detect differencesclearly between two or more compounds in a fluid composition by using amechanical resonator device to measure a composition's physical andelectrical properties.

[0016] It is a further object of the invention to use a mechanicalresonator device to monitor and measure a physical or chemicaltransformation of a fluid composition.

[0017] It is also an object of the invention to use a mechanicalresonator device to detect the presence of a specific material in afluid.

SUMMARY OF THE INVENTION

[0018] The present invention provides methods and apparatus forinterrogating an array of diverse materials located at predefinedregions on a single substrate. Typically, each of the individualmaterials will be screened or interrogated for one or more properties.Once screened, the individual materials may be ranked or otherwisecompared relative to each other with respect to the materialcharacteristics under investigation.

[0019] In one aspect of the invention, systems and methods are providedfor imaging a library of materials using ultrasonic imaging techniques.The system includes one or more devices for exciting an element of thelibrary such that acoustic waves are propagated through, and from, theelement. The acoustic waves propagated from the element are detected andprocessed to yield a visual image of the library element. The acousticwave data can also be processed to obtain information about the elasticproperties of the library element. In one embodiment of the invention,the acoustic wave detector scans the library in a raster pattern, thusproviding a visual image of the entire library.

[0020] In another aspect of the invention, systems and methods areprovided for generating acoustic waves in a tank filled with a couplingliquid. The library of materials is then placed in the tank and thesurface of the coupling liquid is scanned with a laser beam. Thestructure of the liquid surface disturbed by the acoustic wave isrecorded, the recorded disturbance being representative of the physicalstructure of the library. Accordingly, a correspondence between thesurface pattern and the geometry and mechanical properties of thelibrary can be constructed.

[0021] In another aspect of the invention, a probe that includes amechanical resonator is used to evaluate various properties (e.g.,molecular weight, viscosity, specific weight, elasticity, dielectricconstant, conductivity, etc.) of the individual liquid elements of alibrary of materials. The resonator is designed to ineffectively exciteacoustic waves. The frequency response of the resonator is measured forthe liquid element under test, preferably as a function of time. Bycalibrating the resonator to a set of standard liquids with knownproperties, the properties of the unknown liquid can be determined. Anarray of library elements can be characterized by a single scanningtransducer or by using an array of transducers corresponding to thearray of library elements.

[0022] The present invention includes a method for measuring a propertyof a fluid composition using a tuning fork resonator, the methodcomprising:

[0023] placing the tuning fork resonator in the fluid composition suchthat at least a portion of the tuning fork resonator is submerged in thefluid composition;

[0024] applying a variable frequency input signal to a measurementcircuit coupled with the tuning fork resonator to oscillate the tuningfork resonator;

[0025] varying the frequency of the variable frequency input signal overa predetermined frequency range to obtain a frequency-dependentresonator response of the tuning fork resonator; and

[0026] determining the property of the fluid composition based on theresonator response.

[0027] The method can also measure a plurality of fluid compositions,wherein the fluid compositions are liquid compositions, using aplurality of tuning fork resonators, wherein the method furthercomprises:

[0028] providing an array of sample wells;

[0029] placing each of said plurality of liquid compositions in aseparate sample well;

[0030] placing at least one of said plurality of tuning fork resonatorsin at least one sample well;

[0031] applying a variable frequency input signal to a measurementcircuit coupled with each tuning fork resonator in said at least onesample wells to oscillate each tuning fork resonator associated witheach of said at least one sample well;

[0032] varying the frequency of the variable frequency input signal overa predetermined frequency range to obtain a frequency-dependentresonator response of each tuning fork resonator associated with said atleast one sample well; and

[0033] analyzing the resonator response of each tuning fork resonatorassociated with said at least one sample well to measure a property ofeach liquid composition in said at least one sample well.

[0034] Accordingly, the present invention is directed primarily to amethod using a mechanical piezoelectric quartz resonator (“mechanicalresonator”) for measuring physical and electrical properties, such asthe viscosity density product, the dielectric constant, and theconductivity of sample liquid compositions in a combinatorial chemistryprocess. The detailed description below focuses primarily on thicknessshear mode (“TSM”) resonators and tuning fork resonators, but othertypes of resonators can be used, such as tridents, cantilevers, torsionbars, bimorphs, or membrane resonators. Both the TSM resonator and thetuning fork resonator can be used to measure a plurality of compounds ina liquid composition, but the tuning fork resonator has desirableproperties that make it more versatile than the TSM resonator.

[0035] The mechanical resonator is connected to a measuring circuit thatsends a variable frequency input signal, such as a sinusoidal wave, thatsweeps over a predetermined frequency range, preferably in the 25-30 kHzrange for the tuning fork resonator and in a higher range for the TSMresonator. The resonator response over the frequency range is thenmonitored to determine selected physical and electrical properties ofthe liquid being tested. Although both the TSM resonator and the tuningfork resonator can be used to test physical and electrical properties,the tuning fork resonator is an improvement over the TSM resonatorbecause of the tuning fork's unique response characteristics and highsensitivity.

[0036] Both the TSM resonator and the tuning fork resonator can be usedin combinatorial chemistry applications according to the presentinvention. The small size and quick response of the tuning forkresonator in particular makes it especially suitable for use incombinatorial chemistry applications, where the properties of a vastnumber of chemicals must be analyzed and screened in a short timeperiod. In a preferred embodiment, a plurality of sample wellscontaining a plurality of liquid compositions are disposed on an array.A plurality of TSM or tuning fork resonators are dipped into the liquidcompositions, preferably one resonator per composition, and thenoscillated via the measuring circuit. Because the resonatingcharacteristics of both the TSM resonator and the tuning fork resonatorvirtually eliminate the generation of acoustic waves, the size of thesample wells can be kept small without the concern of acoustic wavesreflecting from the walls of the sample wells. In practice, the tuningforks can be oscillated at a lower frequency range than TSM resonators,making the tuning forks more applicable to real-world applications andmore suitable for testing a wide variety of compositions, including highmolecular weight liquids.

[0037] In another embodiment of the invention, the mechanical resonatoris coated with a material to change the resonator's characteristics. Thematerial can be a general coating to protect the resonator fromcorrosion or other problems affecting the resonator's performance, or itcan be a specialized “functionalization” coating that changes theresonator's response if a selected substance is present in thecomposition being tested by the resonator.

[0038] To obtain a more complete range of characteristics for a selectedfluid composition, multiple resonators having different resonatorcharacteristics can be connected together as a single sensor formeasuring the fluid composition. The resonator responses from all of theresonators in the sensor can then be correlated to obtain additionalinformation about the composition being tested. By using resonatorshaving different characteristics, the fluid composition can be testedover a wider frequency range than a single resonator. Alternatively, asingle resonator that can be operated in multiple mechanical modes (e.g.shear mode, torsion mode, etc.) can be used instead of the multipleresonators. The resonator responses corresponding to each mode would becorrelated to obtain the additional information about the composition.

[0039] The mechanical resonator system of the present invention,particularly a system using the tuning fork resonator, can also be usedto monitor changes in a particular liquid by keeping the resonator inthe liquid composition as it undergoes a physical and/or chemicalchange, such as a polymerization reaction. The invention is not limitedto measuring liquids, however; the quick response of the tuning forkresonator makes it suitable for measuring the composition of fluidcompositions, both liquid and vaporous, that are flowing through aconduit to monitor the composition of the fluid.

[0040] A further understanding of the nature and advantages of theinventions herein may be realized by reference to the remaining portionsof the specification and the attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0041]FIG. 1 is an illustration of a transducer-lens system for imaginga library of elements;

[0042]FIG. 2 illustrates an ultrasonic imaging system utilizing apiezoelectric transducer array;

[0043]FIG. 3 illustrates the oscillation mode of a tuning forkresonator;

[0044]FIG. 4 illustrates the oscillation mode of a bimorph/unimorphresonator;

[0045]FIGS. 5a and 5 b are cross-sectional views of a TSM resonatorplate and a tuning fork resonator tine used in preferred embodiments ofthe present invention, respectively;

[0046]FIG. 6 illustrates an embodiment of the invention used todetermine the average molecular weight of polystyrene in toluene duringpolymerization;

[0047]FIG. 7 is a graph of the frequency response of a tuning forkresonator for pure toluene and four different molecular weights ofpolystyrene;

[0048]FIG. 8 is a graph of a calibration curve corresponding to the datashown in FIG. 7;

[0049]FIGS. 9a and 9 b are simplified schematic diagrams illustrating atuning fork resonator connection with the measurement circuit in apreferred embodiment of the present invention;

[0050]FIG. 9c illustrates a sample response of the representativecircuit shown in FIG. 9b;

[0051]FIG. 10 illustrates an embodiment of the invention used for highthroughput screening of catalyst combinatorial libraries; and

[0052]FIG. 11 is a simplified circuit diagram for a multiplexed controlcircuit suitable for use with the embodiment shown in FIG. 10.

[0053]FIGS. 12a and 12 b are examples of traces comparing the frequencyresponses of the TSM resonator and the tuning fork resonator of thepresent invention, respectively;

[0054]FIGS. 13a and 13 b are examples of graphs illustrating therelationship between the viscosity density product and the equivalentserial resistance of the TSM resonator and the tuning fork resonator ofthe present invention, respectively;

[0055]FIGS. 14a and 14 b are examples of graphs illustrating therelationship between the dielectric constant and the equivalent parallelcapacitance of the TSM resonator and the tuning fork resonator of thepresent invention, respectively;

[0056]FIGS. 15a and 15 b are examples of graphs illustrating therelationship between the molecular weight of a sample composition andthe equivalent serial resistance of the TSM resonator and the tuningfork resonator of the present invention, respectively, in apolymerization reaction;

[0057]FIGS. 16a and 16 b illustrate another embodiment of the inventionusing a resonator that is treated with a coating for targeting detectionof specific chemicals; and

[0058]FIGS. 17a, 17 b, and 17 c illustrate examples of differentmultiple resonator sensors of yet another embodiment of the presentinvention.

DETAILED DESCRIPTION

[0059] Glossary

[0060] The following terms are intended to have the following generalmeanings as used herein.

[0061] Substrate

[0062] A substrate is a material having a rigid or semi-rigid surface.In many embodiments at least one surface of the substrate will besubstantially flat. In some embodiments the substrate will containphysical separations between synthesis regions for different materials.Suitable physical separations include, for example, dimples, wells,raised regions, and etched trenches. According to other embodiments,small beads or pellets may be provided on the surface, either alone orwithin substrate surface dimples. The surface area of the substrate isdesigned to meet the requirements of a particular application.Typically, the surface area of the substrate is in the range of 1 cm² to400 cm². However, other sizes may be used with the present invention,for example surface areas as small as 0.001 cm² or as large as 10 m² arepossible.

[0063] Predefined Region

[0064] A predefined region is a localized area on a substrate that is,was, or is intended to be used for the formation of a specific material.The predefined region may be referred to, in the alternative, as a“known” region, a “reaction” region, a “selected” region, or simply a“region.” The predefined region may have any convenient shape, e.g.,linear, circular, rectangular, elliptical, or wedge-shaped.Additionally, the predefined region can be a bead or pellet which iscoated with the component(s) of interest. In this embodiment, the beador pellet can be identified with a tag, such as an etched binary barcode, that can be used to identify which components were deposited onthe bead or pellet. The area of the predefined regions depends on theapplication and is typically smaller than about 25 cm². However, thepredefined regions may be smaller than 10 cm², smaller than 5 cm²,smaller than 1 cm², smaller than 1 mm², smaller than 0.5 mm², smallerthan 10,000 μm², smaller than 1,000 μm², smaller than 100 μm², or evensmaller than 10 μm².

[0065] Radiation

[0066] Radiation refers to energy with a wavelength between 1014 and104. Examples of such radiation include electron beam radiation, gammaradiation, x-ray radiation, ultraviolet radiation, visible light,infrared radiation, microwave radiation, and radio waves. Irradiationrefers to the application of radiation to a surface or an object.

[0067] Component

[0068] Component is used herein to refer to each of the individualsubstances that are deposited onto a substrate. Components can act uponone another to produce a particular material. Components can reactdirectly with each other or with an external energy source such asradiation, an electric field, or a magnetic field. A third material or achemical substance can also act upon components. A component can be anelement, a chemical, a material, or a mixture of elements and chemicals.Components can form layers, blends or mixtures, or combinations thereof.

[0069] Source Material

[0070] The term source material is used herein to refer to the originalmaterial from which a component was derived. Source materials can becomposed of elements, compounds, chemicals, molecules, etc. that aredissolved in a solvent, vaporized, evaporated, boiled, sublimed,ablated, etc., thus allowing the source materials to deposit onto asubstrate during the synthesis process.

[0071] Resulting Material

[0072] The term resulting material is used herein to refer to thecomponent or combination of components that have been deposited onto apredefined region of a substrate. The resulting materials may comprise asingle component, or a combination of components that have reacteddirectly with each other or with an external source. Alternatively, theresulting material may comprise a layer, blend or mixture of componentson a predefined region of the substrate. The resulting materials arescreened for specific properties or characteristics to determine theirrelative performance.

[0073] Mixture or Blend

[0074] The term mixture or, interchangeably, blend refers to acollection of molecules, ions, electrons, or chemical substances. Eachcomponent in the mixture can be independently varied. A mixture canconsist of two or more substances intermingled with no constantpercentage composition, wherein each component may or may not retain itsessential original properties, and where molecular phase mixing may ormay not occur. In mixtures, the components making up the mixture may ormay not remain distinguishable from each other by virtue of theirchemical structure.

[0075] Layer

[0076] The term layer is used herein to refer to a material thatseparates one material, component, substrate or environment fromanother. A layer is often thin in relation to its area and covers thematerial beneath it. A layer may or may not be thin or flat, but once itis deposited it generally covers the entire surface such that itseparates the component or substrate below the layer from the componentor environment above the layer.

[0077] Heterogeneous Catalysts

[0078] Heterogeneous catalysts enable catalytic reactions to occur withthe reactants and catalysts residing in different phases. As usedherein, heterogeneous catalysts include, but are not limited to, mixedmetal oxides, mixed metal nitrides, mixed metal sulfides, mixed metalcarbides, mixed metal fluorides, mixed metal silicates, mixed metalaluminates, mixed metal phosphates, nobel metals, zeolites, metalalloys, intermetallic compounds, inorganic mixtures, inorganiccompounds, and inorganic salts.

[0079] Homogeneous Catalysts

[0080] Homogeneous catalysts enable catalytic reactions to occur withthe reactants and catalysts residing in the same phase. As used herein,homogeneous catalysts include, but are not limited to, catalysts for thepolymerization of one or more olefinic or vinyl monomers. The olefinicmonomers include, but are not limited to, ethylene or alpha-olefinscontaining from 3 to 10 carbon atoms, such as propylene, 1-butene,1-pentane, 1-hexene, and 1-octene. The vinyl monomers include, but arenot limited to, vinyl chloride, vinyl acetate, vinyl acrylate,methylmethacrylate, methyl vinyl ether, ethyl vinyl ether andacetonitrile. The catalysts employed to carry out a polymerization ofone or more monomers of this type include, but are not limited to,radical catalysts, cationic catalysts, anionic catalysts, and anioniccoordination catalysts.

[0081] Generating Arrays of Materials

[0082] Generally, an array of materials is prepared by successivelydelivering components of the materials to predefined regions on asubstrate, and simultaneously reacting the components to form at leasttwo materials or, alternatively, the components are allowed to interactto form at least two materials. In one embodiment, for example, a firstcomponent of a first material is delivered to a first predefinedlocation on a substrate, and a first component of a second material isdelivered to a second predefined region on the same substrate.Simultaneously with or thereafter, a second component of the firstmaterial is delivered to the first region on the substrate, and a secondcomponent of the second material is delivered to the second region onthe substrate. Each component can be delivered in either a uniform orgradient fashion to produce either a single stoichiometry or,alternatively, a large number of stoichiometries within a singlepredefined region. The process is repeated, with additional components,to form a vast array of components at predefined locations on thesubstrate. Thereafter, the components are simultaneously reacted to format least two materials or, alternatively, the components interact toform at least two materials. As described herein, the components can besequentially or simultaneously delivered to the predefined regions onthe substrate using any of a number of different delivery techniques.

[0083] Numerous combinatorial techniques can be used to synthesize thevarious arrays of diverse materials on the substrate according to thepresent invention. For example, in one embodiment a first component of afirst and second material is delivered to the predefined regions on thesubstrate. Then a second component of the first and second materials isdelivered to the predefined regions on the substrate. This processcontinues for the other components (e.g., third, fourth, fifth, etc.components) and/or the other materials (e.g., third, fourth, fifth, etc.materials) until the array is complete. In another embodiment, the arrayis formed as previously described, but the resulting materials areformed immediately as the components contact each other on thesubstrate. In yet another embodiment, the array is formed as previouslydescribed, but after the various components are delivered to thesubstrate, a processing step is carried out which allows or causes thecomponents to interact. In still another embodiment, two or morecomponents are delivered to the predefined regions on the substrateusing fast sequential or parallel delivery techniques such that thecomponents interact with each other before contacting the substrate.

[0084] Essentially, any conceivable substrate can be employed in theinvention. The substrate can be organic, inorganic, biological,nonbiological, or a combination thereof. The substrate can exist in avariety of forms utilizing any convenient shape or configuration. Thesubstrate preferably contains an array of depressions or wells in whichthe synthesis of the library takes place. The substrate preferably formsa rigid support on which to carry out the reactions described herein.The substrate may be any of a wide variety of materials including, forexample, polymers, plastics, Pyrex, quartz, resins, silicon, silica orsilica-based materials, carbon, metals, inorganic glasses, inorganiccrystals, and membranes. Upon review of this disclosure, other substratematerials will be readily apparent to those of skill in the art.Surfaces on the solid substrate can be composed of the same materials asthe substrate or, alternatively, they can be different (i.e., thesubstrates can be coated with a different material). Moreover, thesubstrate surface can contain thereon an adsorbent (for example,cellulose) to which the components of interest are delivered. The mostappropriate substrate and substrate-surface materials will depend on theclass of materials to be synthesized and the selection in any given casewill be readily apparent to those of skill in the art.

[0085] Generally, physical masking systems can be employed incombination with various deposition techniques in order to applycomponents onto the substrate, preferably in an array of wells, in acombinatorial fashion. Thus arrays of resulting materials are createdwithin predefined locations or wells on the substrate. The arrays ofresulting materials will usually differ in composition andstoichiometry. Although the components are typically dispensed in theform of a liquid, one or more components may be dispensed in the form ofa gas or a powder. Therefore primarily solution phase depositiontechniques are used including, for example, sol/gel methods, discreteliquid dispensing techniques (e.g. pipettes, syringes, ink jets, etc.),spin coating with lithography, microcontact printing, spraying withmasks and immersion impregnation. Other techniques may be used, however,such as sputtering, electron-beam and thermal evaporation, laserdeposition, ion beam deposition, chemical vapor deposition, andspray-coating, Dispenser systems can be manual or, alternatively, theycan be automated using, for example, robotics techniques. A descriptionof systems and methods for generating arrays of materials can be foundin commonly assigned, co-pending patent applications “The CombinatorialSynthesis of Novel Materials”, Publication No. WO 95/13278, filed Oct.18, 1995; “Systems and Methods for the Combinatorial Synthesis of NovelMaterials,” patent application Ser. No. 08/841,423, filed Apr. 22, 1997;and “Discovery of Phosphor Materials Using Combinatorial SynthesisTechniques,” provisional patent application Ser. No. 60/039,882, filedMar. 4, 1997; the complete disclosures of which are incorporated hereinby reference for all purposes.

[0086] In some embodiments of the present invention, after thecomponents have been deposited onto or within predefined regions on asubstrate, they are reacted using a number of different techniques. Forexample, the components can be reacted using solution based synthesistechniques, photochemical techniques, polymerization techniques,template directed synthesis techniques, epitaxial growth techniques, bythe sol-gel process, by thermal, infrared or microwave heating, bycalcination, sintering or annealing, by hydrothermal methods, by fluxmethods, by crystallization through vaporization of solvent, etc.Furthermore, each predefined region on the substrate can be heatedsimultaneously or sequentially using heat sources such as focusedinfrared radiation, resistive heating, etc. Reactants can, for example,be dispensed to the library of elements in the form of a gas or aliquid. Other useful techniques that can be used to react the componentsof interest will be readily apparent to those of skill in the art.Additionally, components can react with each other instantly, uponcontacting each other, or in the air before contacting the substrate.

[0087] Once prepared, the array of resulting materials can be screenedfor useful properties and/or the resulting materials can be ranked, orotherwise compared, using the methods described herein. Either theentire array or, alternatively, a section thereof (e.g., a row ofpredefined regions) can be screened using parallel or fast sequentialscreening. The area and/or volume of the predefined regions varies, asdoes the number and density of regions per substrate, depending upon thespecific intended application. Similarly, the number of differentmaterials contained within an array also varies with the intendedapplication. Resulting materials include, but are not limited to,liquids, dissolved organic or inorganic molecules, non-biologicalorganic polymers, polymers partially or fully dissolved in a solvent,covalent network solids, ionic solids and molecular, inorganicmaterials, intermetallic materials, metal alloys, ceramic materials,organic material, organometallic materials, composite materials (e.g.,inorganic composites, organic composites, or combinations thereof), andhomogeneous or heterogeneous catalysts.

[0088] Given the chemical complexity of catalytic systems, the lack ofpredictive models, the number of possible combinations of metals,counter ions, ligands, and supports, and the time consuming process ofevaluating the performance of each catalyst formulation utilizingconventional laboratory pilot reactors, it is not surprising that thesearch for the optimum catalyst is a time consuming and inefficientprocess. Thus, a combinatorial approach to the discovery andoptimization of catalytic systems, which combines the synthesis ofcatalyst libraries with the screening tools of this invention, is usefulfor accelerating the pace of research in this field. The catalystlibraries of the present invention can include organic (e.g., catalyticantibodies), organometallic, heterogeneous or solid state inorganicarray elements. For purposes of this invention, a catalyst is defined asany material that accelerates the rate of a chemical reaction and whichis either not consumed during the reaction or which is consumed at arate slower (on a molar basis) than the reaction that is beingcatalyzed. Organometallic catalyst libraries which can be screened foruseful catalytic properties include, but are not limited to, thosedescribed in co-pending U.S. patent application Ser. No. 08/898,715,filed Jul. 22, 1997, which is hereby incorporated by reference for allpurposes.

[0089] Ultrasonic Imaging

[0090] In this aspect of the invention, systems and methods are providedfor imaging libraries of materials with ultrasonic imaging techniques.In a first embodiment, an acoustic apparatus and method for imaging of alibrary of materials is provided. The apparatus includes a device forgenerating acoustic waves that can propagate into a member or element ofinterest within a library and a detector for sensing the propagation andreflection of the acoustic waves from the library elements. The sourceand the detector of acoustic waves may be the same apparatus, typicallya piezoelectric crystal. After detecting the acoustic waves propagatedfrom the element, the library and the acoustic wave detector are movedrelative to one another, preferably in a raster scanning pattern. Themagnitude and phase of the detected acoustic waves and the correspondingscan pattern of the library are recorded so that visual images of thelibrary can be obtained. In addition, by processing the obtained data inaccordance with a model of sample-acoustic beam interaction, informationabout the elastic properties of individual library members can becalculated. From the relative elastic properties of elements in thelibrary, relative measures of such properties as molecular weight,branching, and co-monomer content may be inferred.

[0091] In a second embodiment of the invention, acoustic waves aregenerated in a tank filled with a coupling liquid using a conventionalmulti-element ultrasound imaging head or one of custom design. Thelibrary of elements is placed within the tank such that acoustic wavesmove from the transducer through the fluid, across the substrate, andinto the elements of the library. The reflections from each interfaceand from within the individual library elements are recorded by theultrasound transducer head. Material properties can be calculated fromthe recorded temporal pattern. Alternatively, the structure ormorphology of the surface of the library elements, or a liquid interfacedeposited on top of them, may be recorded using a laser probe or otherimaging system. Furthermore, since the recorded disturbance isrepresentative of the physical structure of the library, acorrespondence between the surface pattern and the geometry andmechanical properties of the library can be constructed. Lastly, thecollected data can be used to derive microscopic properties ofindividual elements of the library, for example, sound velocity andattenuation as a function of element position can be derived.

[0092] In a third embodiment of the invention, an acoustic lens excitesacoustic waves within elements of the material array. The excitedacoustic waves are in a form of short pulses. The magnitude of theechoes produced by the acoustic waves is measured, as is the time delaybetween the excitation pulses and the echoes from the liquid-materialand material-substrate interfaces. The library and the acoustic wavedetector are moved relative to one another in a raster scanning patternand the collected data is recorded. Based upon the collected data anacoustic image of the library can be generated. The time-resolved imagecan give valuable information about library topography. For example, thefirst echo provides information related to the impedance mismatching onthe element-coupling liquid interface and the second echo providesinformation about the sound velocity distribution in the elementmaterial.

[0093] In a fourth embodiment of the invention, individual piezoelectrictransducers are integrated into the substrate. Typically the transducersare fabricated into the substrate using standard fabrication techniques.The library elements are then deposited onto the substrate such thateach individual library element corresponds to an individualpiezoelectric transducer. The transducers serve the dual function ofexciting the acoustic wave and receiving the return wave.

[0094]FIG. 1 is an illustration of a transducer-lens system coupled to alibrary. The library is comprised of an array of elements 101 containedwithin or on a substrate 103. Substrate 103 is coupled to a tank 105containing a coupling medium 107. Coupling medium 107, selected on thebasis of its acoustic properties, is selected from a variety of liquids,for example, water, mercury, etc. A transducer-lens system 109 providesthe acoustic waves that pass through liquid 107 and are coupled intoelements 101 and substrate 103. Transducer-lens system 109 is also usedto measure the magnitude and time delay between the excitation pulsesand the echoes. If desired, the excitation transducer may be separatefrom the receiving transducer. As described above, transducer-lens 109is scanned across the array in order to obtain information about theentire array. Alternatively, an array of transducer-lenses may be used(not shown) as is used in conventional ultrasound imaging.

[0095]FIG. 2 illustrates a combinatorial library synthesized on asubstrate consisting of integrated piezoelectric transducers. In thepreferred embodiment, the individual piezoelectric transducers 201comprising the transducer array are directly incorporated into substrate103. Each transducer 201 is aligned such that it is directly adjacent toa corresponding library element 101. Transducers 201 serve as both thetransmitters and receivers of the acoustic energy. The output signalsfrom transducers 201 can be multiplexed for serial readout. In analternative embodiment, transducers 201 are mounted onto a separatesubstrate (not shown) that is brought into contact with substrate 103.In another alternative embodiment, substrate 103 is formed of apiezoelectric material and electrodes are attached directly under eachlibrary element (not shown).

[0096] Mechanical Oscillator Probes

[0097] Although ultrasonic transducers can be used to determine avariety of material properties, this technique is not suitable for allliquids. Typically the size of the transducer and the cell should bemuch greater than the acoustic wavelength; otherwise the diffractioneffects and steady waves within the cell become too complicated. For acell on the order of a few centimeters, the frequency should be above 1MHz. However complex liquids and solutions, such as polymer solutions,often behave like elastic gels at high frequencies due to theirrelaxation time corresponding to significantly lower frequencies.

[0098] The method and apparatus of the present invention focuses onusing a mechanical resonator to generate and receive oscillations in afluid composition for testing its characteristics in a combinatorialchemistry process or other process requiring analysis of the fluidcomposition's physical and/or chemical properties. Although the detaileddescription focuses on combinatorial chemistry and the measurement of aliquid composition's characteristics, the invention can be used in anyapplication requiring measurement of characteristics of a fluidcomposition, whether the fluid is in liquid or vapor form. The fluidcomposition itself can be any type of fluid, such as a solution, aliquid containing suspended particulates, or, in some embodiments, evena vapor containing a particular chemical or a mixture of chemicals. Itcan also include a liquid composition undergoing a physical and/orchemical change (e.g. an increase in viscosity).

[0099] Shear-mode transducers as well as various surface-wavetransducers can be used to avoid some of the problems associated withtypical ultrasonic transducers. Since leaky surface acoustic waves decayexponentially with the distance from the sensor surface, such sensorstend to be insensitive to the geometry of the measurement volume, thuseliminating most diffraction and reflection problems. Furthermore, suchsensors are cheap, reproducible, and can be used to construct highthroughput screening devices. Unfortunately the operation frequency ofthese sensors is also high, thus restricting their applicability asmentioned above. Moreover, at such frequencies only a very thin layer ofliquid near the sensor surface will influence the response of thesensor. Thus modification of the surface of the sensor throughadsorption of solution components will often result in dramatic changesin properties associated with the sensor.

[0100] To eliminate the effects of diffraction, acoustic waveinterference, and measurement cell geometry, it is preferable to use atransducer or sensor that does not excite acoustic waves. A sensor thatis much smaller than the wavelength accomplishes these goals, providingan oscillator that ineffectively excites acoustic waves in thesurrounding media. Designing the different parts of the sensor tooscillate in opposite phases can enhance this effect. In such aresonator most of the mechanical energy associated with the oscillationdissipates due to the viscosity, both shear and bulk, of the liquidinvolved in the oscillatory motion. The sensor produces a hydrodynamicflow velocity field that decays with the distance from sensor. Thusliquid at a distance a few times greater than the sensor dimensionremains practically unperturbed. If the measurement cell is large enoughto contain the field of perturbation, the device becomes insensitive tothe cell geometry. Examples of suitable oscillators include piezoceramicand quartz resonators embodied in the form of a tuning fork, a unimorph,or a bimorph. FIGS. 3 and 4 illustrate the oscillation modes of tuningfork and bimorph/unimorph resonators, respectively.

[0101] Typically a system according to the invention uses an AC voltagesource to excite oscillation of the resonator. The system also includesa receiver which measures the frequency response of the resonator in theliquid under test. The response of the resonator varies depending uponthe viscosity, specific weight, and elasticity of the liquid under test.In some cases the dielectric constant and the conductivity of the liquidcan influence the response of the resonator. If properties of the liquidvary with time, the response of the resonator will similarly vary. Bycalibrating the resonator to a set of standard liquids with knownproperties, the properties of an unknown liquid can be determined fromthe response of the resonator.

[0102] Mechanical resonators, such as thickness shear mode (TSM) quartzresonators 10, are used in the present invention for measuring variousphysical properties of fluid compositions, such as a liquid's viscosity,molecular weight, specific weight, etc., in a combinatorial chemistrysetting or other liquid measurement application. Referring to FIG. 5a,TSM resonators 10 usually have a flat, plate-like structure where aquartz crystal 12 is sandwiched in between two electrodes 14. Incombinatorial chemistry applications, the user first generates a“library”, or large collection, of compounds in a liquid composition.Normally, each liquid composition is placed into its own sample well. ATSM resonator 10 connected to an input signal source (not shown) isplaced into each liquid composition, and a variable frequency inputsignal is sent to each TSM resonator 10, causing the TSM resonator 10 tooscillate. The input signal frequency is swept over a predeterminedrange to generate a unique TSM resonator 10 response for each particularliquid. Because every compound has a different chemical structure andconsequently different properties, the TSM resonator 10 response will bealso be different for each compound. The TSM resonator response is thenprocessed to generate a visual trace of the liquid composition beingtested. An example of traces generated by the TSM resonator 10 formultiple liquid compositions is shown in FIG. 12a. Screening andanalysis of each compound's properties can then be conducted bycomparing the visual traces of each compound with a reference and/orwith other compounds. In this type of application, the TSM resonator 10serves both as the wave source and the receiver.

[0103] Two types of waves can be excited in liquids: compression waves(also called acoustic waves), which tend to radiate a large distance, onthe order of hundreds of wavelengths, from the wave-generating source;and viscose shear waves, which decay almost completely only onewavelength away from the wave-generating source. In any liquid propertytesting, acoustic waves should be kept to a minimum because they willcreate false readings when received by the resonator due to their longdecay characteristics. For typical prior art ultrasonictransducers/resonators, the resonator oscillation creates acoustic wavesthat radiate in all directions from the resonator, bounce off the sidesof the sample well, and adversely affect the resonator response. As aresult, the resonator response will not only reflect the properties ofthe liquid being measured, but also the effects of the acoustic wavesreflecting from the walls of the sample well holding the liquid, therebycreating false readings. Using a sample well that is much greater thanthe acoustic wavelength does minimize the negative effects of acousticwaves somewhat, but supplying thousands of sample wells having suchlarge dimensions tends to be impractical.

[0104] TSM resonators 10 primarily generate viscose shear waves and aretherefore a good choice for liquid property measurement in combinatorialchemistry applications because they do not generate acoustic waves thatcould reflect off the sides of the sample wells and generate falsereadings. As a result, the sample wells used with the TSM resonators 10can be kept relatively small, making it feasible to construct an arrayof sample wells for rapid, simultaneous testing of many liquids. Thehigh stiffness of TSM resonators 10, however, requires them to beoperated at relatively high frequencies, on the order of 8-10 MHz. Thisstiffness does not adversely affect measurement accuracy for manyapplications, though, making the TSM resonator an appropriate choice formeasuring numerous liquid compositions.

[0105] However, TSM resonators 10 can be somewhat insensitive to thephysical properties of certain liquids because the load provided by thesurrounding liquid is less than the elasticity of the resonator. Moreparticularly, the high operating frequencies of TSM resonators 10 makethem a less desirable choice for measuring properties of certain liquidcompositions, particularly high-molecular weight materials such aspolymers. When high frequency waves are propagated through highmolecular-weight liquids, the liquids tend to behave like gels becausethe rates at which such large molecules move correspond to frequenciesthat are less than that of the TSM resonator's oscillations. This causesthe TSM resonator 10 to generate readings that sometimes do not reflectthe properties at which the liquids will actually be used (mostmaterials are used in applications where the low-frequency dynamicresponse is most relevant). Although it would be more desirable tooperate the TSM resonator 10 at lower frequencies so that laboratoryconditions reflect real world conditions, the stiffness of the TSMresonator 10 and its resulting high operating frequencies can makeoperation at lower frequencies rather difficult. Further, even when theTSM resonator 10 can accurately measure a liquid's properties, thedifferences in the visual traces associated with different compositionsare relatively slight, making it difficult to differentiate betweencompositions having similar structures, as shown in FIG. 12a.

[0106] TSM resonators and other plate-type resonators, while adequate,may not always be the best choice for measuring the electricalcharacteristics, such as the dielectric constant, of the liquidcomposition being measured. As shown in FIG. 5a, the cross-section of aTSM resonator 10 has the same structure as a flat capacitor, resultingin relatively little coupling between the electric field of theresonator and the surrounding composition. While there can be enoughelectrical coupling between the resonator and the composition to measurethe composition's electrical properties, a greater amount of electricalcoupling is more desirable for increased measurement accuracy.Electrical coupling will be explained in greater detail below whencomparing the electrical characteristics between the TSM resonator 10and the tuning fork resonator 20.

[0107]FIGS. 5a and 5 b show a cross-section of a TSM resonator plate 10and a tuning fork tine 22, respectively. The tuning fork resonator 20 ispreferably made from a quartz crystal 24 and has two tines 22, asrepresented in FIG. 3, each tine having the quartz crystal center 24 andat least one electrode 26 connected to the quartz crystal 24. The tuningfork tines 22 in the preferred structure have a square or rectangularcross-section such that the quartz crystal center 24 of each tine hasfour faces. The electrodes 26 are then attached to each face of thequartz crystal center 24, as shown in FIG. 5b. The method and system ofthe present invention can use any type of tuning fork resonator, such asa trident (three-prong) tuning fork or tuning forks of different sizes,without departing from the spirit and scope of the invention.

[0108] The cross-sectional views of the TSM resonator 10 and the tuningfork resonator 20 shown in FIGS. 5a and 5 b also illustrate the relativedifferences between the electric coupling of each resonator with thesurrounding liquid. Referring to FIG. 5a, the structure of the TSMresonator 10 is very flat, making it close to a perfect capacitor whenit is placed in the liquid to be measured. As noted above, the quartzcrystal 12 in the TSM resonator 10 is sandwiched between two electrodes14, causing most of an electric field 16 to travel between the twoelectrodes through the quartz crystal 12. Because most of the electricfield 16 is concentrated within the quartz crystal 12 rather thanoutside of it, there is very little electric coupling between the TSMresonator 10 and the surrounding liquid except at the edges of theresonator 10. While there may be sufficient electrical coupling tomeasure the electrical properties, such as the conductivity ordielectric constant, of the liquid composition being tested, a greaterdegree of coupling is desirable to ensure more accurate measurement.

[0109] By comparison, as shown in FIG. 5b, the structure of each tuningfork tine 22 allows much greater electrical coupling between the tine 22and the surrounding liquid because the tuning fork tine'scross-sectional structure has a much different structure than a flatcapacitor. Because the tuning fork tine 22 is submerged within theliquid being tested, an electric field 27 associated with each tine 22does not concentrate in between the electrodes 24 or within the quartzcrystal 24, but instead interacts outside the tine 22 with thesurrounding liquid. This increased electrical coupling allows the tuningfork 20 to measure accurately the electrical properties of the liquid aswell as its physical properties, and it can measure both types ofproperties simultaneously if so desired.

[0110] One unexpected result of the tuning fork resonator 20 is itsability to suppress the generation of acoustic waves in a liquid beingtested, ensuring that the resonator's 20 physical response will be basedonly on the liquid's physical properties and not on acoustic waveinterference or the shape of the sample well holding the liquid. Asexplained above, TSM resonators 10 minimize excitation of acoustic wavesbecause it generates shear oscillations, which do not excite wavesnormal to the resonator's surface. As also explained above, however, theTSM resonator 10 requires high frequency operation and is not suitablefor many measurement applications, particularly those involvinghigh-molecular weight liquids.

[0111] Without wishing to be bound by any particular theory, theinventors believe that the tuning fork resonator 20 used in the presentinvention virtually eliminates the effects of acoustic waves withouthaving to increase the size of the sample wells to avoid wavereflection. Tuning fork resonators 20, because of their shape and theirorientation in the liquid being tested, contain velocity componentsnormal to the vibrating surface. Thus, it was assumed in the art thattuning fork resonators were unsuitable for measuring liquid propertiesbecause they would generate acoustic waves causing false readings. Inreality, however, tuning fork resonators 20 are very effective insuppressing the generation of acoustic waves for several reasons. First,the preferred size of the tuning fork resonator 20 used in the inventionis much smaller than the wavelength of the acoustic waves that arenormally generated in a liquid, as much as one-tenth to one-hundredththe size. Second, as shown in FIG. 3, the tines 22 of the tuning forkresonator 20 oscillate in opposite directions, each tine 22 acting as aseparate potential acoustic wave generator. In other words, the tines 22either move toward each other or away from each other. Because the tines22 oscillate in opposite directions and opposite phases, however, thewaves that end up being generated locally by each tine 22 tend to canceleach other out, resulting in virtually no acoustic wave generation fromthe tuning fork resonator 22 as a whole.

[0112] A simplified diagram of one example of the inventive mechanicalresonator 20 system is shown in FIG. 6. Although the explanation of thesystem focuses on using the tuning fork resonator 20, the TSM resonator10 described above can also be used for the same purpose. To measure theproperty of a given liquid, the tuning fork resonator 20 is simplysubmerged in the liquid to be tested. A variable frequency input signalis then sent to the tuning fork resonator using any known means tooscillate the tuning fork, and the input signal frequency is swept overa predetermined range. The tuning fork resonator's response is monitoredand recorded. In the example shown in FIG. 6, the tuning fork resonator20 is placed inside a well 26 containing a liquid to be tested. Thisliquid can be one of many liquids for comparison and screening or it cansimply be one liquid whose properties are to be analyzed independently.Further, if there are multiple liquids to be tested, they can be placedin an array and measured simultaneously with a plurality of tuning forkresonators to test many liquids in a given amount of time. The liquidcan also be a liquid that is undergoing a polymerization reaction or aliquid flowing through a conduit.

[0113] The tuning fork resonator 20 is preferably coupled with a networkanalyzer 28, such as a Hewlett-Packard 8751A network analyzer, whichsends a variable frequency input signal to the tuning fork resonator 20to generate the resonator oscillations and to receive the resonatorresponse at different frequencies. The resonator output then passesthrough a high impedance buffer 30 before being measured by a wide bandreceiver 32. The invention is not limited to this specific type ofnetwork analyzer, however; any other analyzer that generates andmonitors the resonator's response over a selected frequency range can beused without departing from the scope of the invention. For example, asweep generator and AC voltmeter can be used in place of the networkanalyzer.

[0114] In one embodiment of the invention illustrated in FIG. 6, atuning fork resonator system 500 is used to monitor the averagemolecular weight of polystyrene in toluene solutions duringpolymerization reactions. This configuration is not limited to thispolymerization reaction; rather, the polymerization reaction is simplyused as an example of an application of this embodiment. The monitoringof the forming polymer's properties in the presence of a polymerizationcatalyst and possibly a solvent is essential in order to estimatecatalytic activity and conversion rate.

[0115] In use, a tuning fork resonator 501 is placed within a well 503containing the liquid to be tested. Preferably well 503 is one well of aplurality of wells contained within an array. Resonator 501 is typicallycoupled to a probe and the probe is scanned from sample well to samplewell in a raster fashion. Alternatively, an array of resonator probescan be fabricated corresponding to the array of wells or some subsetthereof, thus allowing a large number of wells to be simultaneouslytested. In the embodiment illustrated in FIG. 6, a network analyzer 505,such as a HP8751A Analyzer, is used to excite the resonator oscillationsand to receive the response of the oscillator at various frequencies.Resonator response is then recorded as a function of excitationfrequency. The output signal of resonator 501 passes through a highimpedance buffer amplifier 507 prior to being measured by the analyzer'swide band receiver 509.

[0116] System 500 was calibrated using a set of standard solutions ofpolystyrene at a constant concentration of 52 mg/ml. In pure toluene,the frequency of the resonator fundamental mode was 28 kHz. FIG. 7 is agraph of the frequency responses of resonator 501 for pure toluene andfour different molecular weights of polystyrene. The distance betweenthe frequency response curve for toluene and an i-polymer solution wascalibrated using the set of different molecular weights. This distanceis given by:$d_{i} = \left( {\frac{1}{f_{1} - f_{0}}{\int_{f_{0}}^{f_{1}}{\left( {R_{0} - R_{i}} \right)^{2}\quad {f}}}} \right)^{\frac{1}{2}}$

[0117] where f₀ and f₁, are the start and stop frequencies,respectively, R₀ is the frequency response of the resonator in toluene,and R₁ is the resonator response in the i-polymer solution.

[0118]FIG. 8 is a graph of a calibration curve corresponding to thisdata. The test points and associated error bars are indicated on thiscurve. Obviously additional calibration curves can be taken asnecessary. The graph of FIG. 8 shows that for this particular resonatordesign, the best accuracy is achieved for molecular weights in the rangeof 10,000 to 100,000.

[0119] To monitor a polymerization reaction, resonator probe 501 isplaced in a measurement well 503 filled with pure toluene and thecatalyst. The frequency response of the sensor for this solution isrecorded. Resonator probe 501 is then placed in a measurement well 503filled with toluene in which a low molecular weight polystyrene has beendissolved. After the catalyst is added, the frequency response of theresonator is recorded at intervals, typically between 10 and 30 seconds.The distance of the response curve for the polymer from that of puretoluene is then calculated in accordance with the formula given above.The molecular weight of the polymer is calculated using the calibrationcurve of FIG. 8.

[0120] As discussed above, depending upon the liquid to be tested, otherresonator designs may be used. For example, to improve the suppressionof acoustic waves, a tuning fork resonator with four tines can be used.It is also possible to excite resonator oscillations through the use ofvoltage spikes instead of a frequency sweeping AC source. In this casethe decaying free oscillations of the resonator are recorded instead ofthe frequency response. A variety of signal processing techniques wellknown by those of skill in the art can be used.

[0121] An equivalent circuit of the tuning fork resonator 20 and itsassociated measurement circuit is represented in FIGS. 9a and 9 b. FIG.9a represents an illustrative tuning fork resonator system that measuresa liquid's viscosity and dielectric constant simultaneously, while FIG.9b represents a tuning fork resonator system that can also measure aliquid's conductivity as well. Referring to FIG. 9a, the measurementcircuit includes a variable frequency input signal source 42, and theresonator equivalent circuit 43 contains series capacitor Cs, resistorRs, inductor L, and parallel capacitor Cp. The resonator equivalentcircuit 43 explicitly illustrates the fact that the quartz crystal 24 inthe tuning fork resonator 20 acts like a capacitor Cp. Therepresentative circuit 40 also includes input capacitor Cin, inputresistor Rin and an output buffer 44.

[0122] The representative circuit shown in FIG. 9b adds a parallelresistor Rp in parallel to capacitor Cp to illustrate a circuit thatmeasures conductivity as well as dielectric constant and viscosity,preferably by comparing the equivalent resistance found in a givenliquid with a known resistance found via calibration. These conceptswill be explained in further detail below with respect to FIGS. 12a-b,13 a-b, 14 a-b, and 15 a-b. Rp represents the conductivity of the liquidbeing tested. The resistance can be calibrated using a set of liquidshaving known conductivity and then used to measure the conductivity of agiven liquid. For example, FIG. 4c shows a sample trace comparing theresonator response in pure toluene and in KaBr toluene solution. Aliquid having greater conductivity tends to shift the resonator responseupward on the graph, similar to liquids having higher dielectricconstants. However, unlike liquids with higher dielectric constants, aliquid having greater conductivity will also cause the resonatorresponse to level out somewhat in the frequency sweep, as can be seen inthe upper trace 45 between 30 and 31.5 kHz. In the example shown in FIG.9c, the difference between the upper trace 45 and the lower trace 46indicates that the equivalent resistance Rp caused by the additionalKaBr in solution was about 8 mega-ohms.

[0123]FIG. 10 illustrates an embodiment of the invention that can beused for high throughput screening of catalyst combinatorial libraries.The embodiment monitors the molecular weight and concentration, ifnecessary, of a polymer in a solution in the presence of differentcatalysts while the reactions are running. Preferably the system alsoincludes means for monitoring the heat generated during the reactions.Thus hundreds of catalysts can be evaluated in a single experiment forsuch characteristics as selectivity, conversion rate, etc.

[0124] An array of measurement wells 801 is contained within a substrate803. Within each well 801 is a resonator 805 for molecular weightdetermination and a thermistor 807 for heat of reaction determination.Preferably contacts 809 for resonator 805 and thermistor 807 passthrough the bottom of substrate 803 where they are connected to thenecessary electronics. Much of the electronics can be mounted directlyto the bottom of substrate 803, simplifying the overall system design.However, as previously described, the array of resonator probes can alsobe fabricated as a stand alone array to be placed within thecorresponding measurement wells of a combinatorial library array duringtesting.

[0125] The measurement package within each well 801 may also contain anagitator 811 to insure uniform concentration distribution within thewell. Typically agitator 811 is not required if well 801 is small enoughto promote rapid concentration leveling due to diffusion. Besidesmonitoring the heat generated during the reactions, thermistors 807 mayalso be used to preheat the media within wells 801 up to a predefinedtemperature and to keep the temperature at the same level during thereactions. In a specific embodiment, a thermostatically controlledcooling liquid 813 passes between the walls of wells 801, thus providinga steady heat transfer from wells 801.

[0126]FIG. 11 is a simplified circuit diagram for a multiplexed controlcircuit suitable for use with the embodiment shown in FIG. 10. Althoughonly three measurement cells 901 are shown, this control circuit can beused to multiplex a large array of cells. The output of a resonator 903passes through a local buffer amplifier 905 before being multiplexedinto a data acquisition system 907. Coupled to each thermistor 909 is athermostat 911. The heat produced by a reaction causes local thermostat911 to drop down the voltage across thermistor 909 to keep itstemperature at the same level. As with the resonator output, thisvoltage is multiplexed and acquired by data acquisition system 907. Thusthe heat production given by each reaction can be easily calculated atany time, providing information about the activity of a particularcatalyst. The data acquired by system 907 is processed by processor 913and presented to the user via monitor 915. The data may also be storedin memory resident within processor 913. From this data the reactionsoccurring in the various wells may be simultaneously characterized.

[0127] In an alternate embodiment, multiple resonators are used withineach single well of an array. The multiple resonators typically have adifferent resonance frequency and/or geometry. This embodiment offersseveral advantages to the previous embodiment utilizing a singleresonator per well. First, the dynamic sensing range of the system maybe greatly extended since each of the individual resonators may bedesigned to cover a different frequency range. Second, the sensitivityover the sensing range may be enhanced since each resonator may bedesigned to be sensitive to a different frequency range. For example,the graph illustrated in FIG. 8 shows that for this particular resonatordesign, the best accuracy was achieved for molecular weights in therange of 10,000 to 100,000. Utilizing the present embodiment, aresonator with the accuracy shown above could be combined in a singlesample well with a resonator having improved accuracy in the 100,000 to1,000,000 range, thus providing superlative sensing capabilitiesthroughout the 10,000 to 1,000,000 range for a single sample well. Thesignals from the independent resonators may be analyzed using suchmethods as neural networks, etc.

[0128]FIGS. 12a-b, 13 a-b, 14 a-b and 15 a-b are examples demonstratingthe effectiveness of the invention. These figures show some differencesbetween the frequency responses, for various liquid compositions, of theplate-type TSM resonator 10 and the tuning fork resonator 20. FIGS. 12a,13 a, 14 a and 15 a are examples using the TSM resonator 10, and FIGS.12b, 13 b, 14 b and 15 b are examples using the tuning fork resonator20.

[0129] The experimental conditions for generating the example tuningfork resonator traces in FIGS. 12b, 13 b, 14 b, and 15 b are describedbelow. The experimental conditions for generating the comparative TSMresonator traces in FIGS. 12a, 13 a, 14 a and 15 a are generally similarto, if not the same as, the conditions for the tuning fork resonatorexcept for, if needed, minor modifications to accommodate the TSMresonator's particular geometry. Therefore, for simplicity and clarity,the TSM resonator's particular experimental conditions will not bedescribed separately.

[0130] All of the solvents, polymers and other chemicals used in theillustrated examples were purchased from Aldrich, and the polymersolutions were made according to standard laboratory techniques. Drypolymers and their corresponding solvents were weighed using standardbalances, and the polymer and solvent were mixed until the polymerdissolved completely, creating a solution having a known concentration.The solutions were delivered to and removed from a 30 ul stainless steelcylindrical measurement well that is long enough to allow a tuning forkresonator to be covered by liquid. Liquid delivery and removal to andfrom the well was conducted via a pipette or syringe.

[0131] Before any experiments were conducted with the solutions, thetuning fork resonator response in air was measured as a reference. Theactual testing processes were conducted in a temperature-controlledlaboratory set at around 20 degrees Centigrade. Once the liquid wasdelivered to the well, the tuning fork was placed in the well and thesystem was left alone to allow the temperature to stabilize.Alternatively, the tuning fork can be built into a wall portion or abottom portion of the well with equally accurate results. The tuningfork was then oscillated using the network analyzer. The resonatorresponse was recorded during each measurement and stored in a computermemory. The measured response curve was fitted to a model curve using anequivalent circuit, which provided specific values for the equivalentcircuit components described above with respect to FIGS. 9a and 9 b andthe traces in FIGS. 13a through 15 b.

[0132] After the measurement of a given solution was completed, theresonator was kept in the well and pure solvent was poured inside thewell to dissolve any polymer residue or coating in the well and on thetuning fork. The well and tuning fork were blown dry using dry air, andthe tuning fork response in air was measured again and compared with theinitial tuning fork measurement to ensure that the tuning fork wascompletely clean; a clean tuning fork would give the same response asthe initial tuning fork response. Note that the above-describedexperimental conditions are described only for purposes of illustrationand not limitation, and those of ordinary skill in the art wouldunderstand that other experimental conditions can be used withoutdeparting from the scope of the invention.

[0133] Although both the TSM resonator 10 and the tuning fork resonator20 are considered to be part of the method and system of the presentinvention, the tuning fork resonator 20 has wider application than theTSM resonator 10 and is considered by the inventors to be the preferredembodiment for most measurement applications because of its sensitivity,availability and relatively low cost. For example, note that in FIGS. 5aand 5 b, the frequency sweep for the TSM resonator 10 is in the 8 MHzrange, while the frequency sweep for the tuning fork resonator 20 of thepresent invention is in the 25-30 kHz range, several orders of magnitudeless than the TSM resonator frequency sweep range. This increases theversatility and applicability of the tuning fork resonator 20 formeasuring high molecular weight liquids because the operating frequencyof the tuning fork resonator 20 is not high enough to make highmolecular weight liquids act like gels. Further, because mostapplications for the solutions are lower frequency applications, thelaboratory conditions in which the liquid compositions are tested usingthe tuning fork resonator 20 more closely correspond with real-worldconditions.

[0134] Also, the operating frequency of the tuning fork resonator 20varies according to the resonator's geometry; more particularly, theresonance frequency of the tuning fork 20 depends on the ratio betweenthe tine cross-sectional area and the tine's length. Theoretically, itis possible to construct a tuning fork resonator 20 of any length for agiven frequency by changing the tuning fork's cross-sectional area tokeep the ratio between the length and the cross-section constant. Inpractice, however, tuning fork resonators 20 are manufactured fromquartz wafers having a few selected standard thicknesses. Therefore, thecross-sectional area of the tuning fork 20 tends to be limited based onthe standard quartz wafer thicknesses, forcing the manufacturer tochange the tuning fork's resonating frequency by changing the tinelength. These manufacturing limitations must be taken into account whenselecting a tuning fork resonator 20 that is small enough to fit inminimal-volume sample wells (because the chemicals used are quiteexpensive) and yet operates at a frequency low enough to prevent thetested liquids from acting like gels. Of course, in other applications,such as measurement of liquids in a conduit or in other containers, theoverall size of the tuning fork resonator 20 is not as crucial, allowinggreater flexibility in selecting the size and dimensions of the tuningfork resonator 20. Selecting the actual tuning fork dimensions anddesigning a tuning fork resonator in view of manufacturing limitationsare tasks that can be conducted by those of skill in the art afterreviewing this specification.

[0135] Referring to FIGS. 12a and 12 b, the solutions used as examplesin FIGS. 12a and 12 b have somewhat similar structures and weights. As aresult, the TSM resonator responses for each solution, shown in FIG.12a, create very similar traces in the same general range. Because thetraces associated with the TSM resonator 10 overlap each other to such agreat extent, it is difficult to isolate and compare the differencesbetween the responses associated with each solution. By comparison, asshown in FIG. 17b, the increased sensitivity of the tuning forkresonator 20 causes small differences in the chemical structure totranslate into significant differences in the resonator response.Because the traces generated by the tuning fork resonator 20 are sodistinct and spaced apart, they are much easier to analyze and compare.

[0136] Using a tuning fork resonator 20 to measure properties of liquidsalso results in greater linearity in the relationship between the squareroot of the product of the liquid's viscosity density and the equivalentserial resistance Rs (FIGS. 13a and 13 b) as well as in the relationshipbetween the dielectric constant and the equivalent parallel capacitanceCp (FIGS. 14a and 14 b) compared to TSM resonators 10. For example, therelationship between the liquid viscosity and serial resistance for atuning fork resonator 20, as shown in FIG. 13b, is much more linear thanthat for the TSM resonator, as shown in FIG. 13a.

[0137] Similarly, the relationship between the dielectric constant andthe equivalent parallel capacitance is more linear for a tuning forkresonator 20, as shown in FIGS. 14a and 14 b. This improved linearrelationship is primarily due to the relatively low frequencies at whichthe tuning fork resonator 20 operates; because many liquids exhibitdifferent behavior at the operating frequencies required by the TSMresonator 10, the TSM resonator 10 will tend not to generate testingresults that agree with known data about the liquids' characteristics.

[0138]FIGS. 15a and 15 b illustrate sample results from real-timemonitoring of polymerization reactions by a TSM resonator and a tuningfork resonator, respectively. The graphs plot the equivalent resistanceRs of the resonators oscillating in 10 and 20 mg/ml polystyrene-toluenesolutions versus the average molecular weight of polystyrene. Asexplained above, high molecular weight solutions often exhibit differentphysical characteristics, such as viscosity, at higher frequencies.

[0139] The size and shape of the TSM resonator 10 make the resonatorsuitable, but not as accurate, for real-time monitoring ofpolymerization reactions compared with the tuning fork resonator 20.This is because the TSM resonator's high operating frequency reduces theaccuracy of measurements taken when the molecular weight of thepolymerizing solution increases. As shown in FIG. 15a, a high operatingfrequency TSM resonator is not very sensitive in monitoring themolecular weight of the polystyrene solution used in the illustratedexample. A tuning fork resonator, by contrast, has greater sensitivityto the molecular weight of the solution being measured, as shown in FIG.15b. This sensitivity and accuracy makes it possible, for manyreactions, to estimate the amount of converted solution in thepolymerization reaction and use the conversion data to estimate theaverage molecular weight of the polymer being produced.

[0140] Although the above-described examples describe using a TSM or atuning fork resonator without any modifications, the resonator can alsobe treated with a “functionality” (a specialized coating) so that it ismore sensitive to certain chemicals. The resonator may also be treatedwith a general coating to protect the resonator from corrosion or otherproblems that could impede its performance. A representative diagram ofan embodiment having a functionalized resonator is shown in FIGS. 16aand 16 b. Although FIGS. 16a and 16 b as well as the followingdescription focuses on coating or functionalizing a tuning forkresonator, any other mechanical resonator can also be used withoutdeparting from the scope of the invention.

[0141] The tuning fork resonator 20 can be coated with a selectedmaterial to change how the resonator 20 is affected by a fluidcomposition (which, as explained earlier, includes both liquid and vaporcompositions). As mentioned above, one option is a general coating forproviding the tuning fork resonator 20 with additional properties suchas corrosion resistance, chemical resistance, electrical resistance, andthe like. Another option, as noted above, is using a “functionality”,which coats the tines with materials that are designed for a specificapplication, such as proteins to allow the tuning fork resonator 20 tobe used as a pH meter or receptors that attract specific substances inthe fluid composition to detect the presence of those substances. Thecoating or functionality can be applied onto the tuning fork resonator20 using any known method, such as spraying or dipping. Further, thespecific material selected for the coating or functionality will dependon the specific application in which the tuning fork resonator 20 is tobe used. J. Hlavay and G. G. Guilbault described various coating andfunctionalization methods and materials to adapt piezoelectric crystaldetectors for specific applications in “Applications of thePiezoelectric Crystal Detector in Analytical Chemistry,” AnalyticalChemistry, Vol. 49, No. 13, November 1977, p. 1890, incorporated hereinby reference. For example, applying different inorganic functionalitiesto the tuning fork resonator 20 allows the resonator to detectorganophosphorous compounds and pesticides.

[0142] An example of a tuning fork resonator that has undergone afunctionalization treatment is illustrated in FIGS. 16a and 16 b. FIG.16a represents a tuning fork tine 22 that has been treated by absorbing,coating, or otherwise surrounding the tine 22 with a functionalitydesigned to change the tuning fork's resonance frequency after beingexposed to a selected target chemical. In the illustrated example, thetuning fork tine 22 is covered with receptor molecules 90, representedin FIGS. 16a and 16 b by Y-shaped members, designed to bond withspecific target molecules. Because the resonance frequency and thedamping of the tuning fork resonator depends on the effective mass ofthe tine 22 and the amount of “drag” of the tine 22 within the fluid,any change in the tine's mass or the amount of drag will change thetuning fork's resonance response. More specifically, the resonancefrequency of the tuning fork resonator is proportional to the squareroot of the inverse of the tuning fork's mass. An increase in the tuningfork's mass will therefore reduce the tuning fork's resonance frequency.

[0143] This mass-frequency relationship is used to detect the presenceof a specific target chemical in a fluid composition in this example.When the functionalized tuning fork tine 22 is placed in a fluidcomposition containing the target chemical, the receptors 90 on thetuning fork tine 22 will chemically bond with molecules of the targetchemical 92, as shown in FIG. 16b. The resonance frequency of the tuningfork resonator will consequently decrease because of the increased massand the additional drag created by the additional molecules 92 attachedto the tuning fork tines 22 via the receptor molecules 90. Thus, whenscreening a plurality of fluid compositions to detect the presence of atarget chemical in any of them, only the fluid compositions containingthe target chemical will cause the tuning fork's resonance frequency tochange. Fluid compositions without the target chemical will not containmolecules that will bond with the receptor molecules 90 on the tuningfork tine 22, resulting in no resonance frequency change for thosefluids. Alternatively, the tuning fork tines 22 can be functionalizedwith a material that physically changes when exposed to molecules of aselected chemical such that the material changes the mechanical drag onthe tuning fork tine 22 when it is exposed to the selected chemical. Forexample, adding a hydrophobic or hydrophilic functionality to the tuningfork tine 22 allows the tine 22 to attract or repel selected substancesin the medium being analyzed, changing the mass or effective mass of thetuning fork and thereby changing its resonance frequency.

[0144] In yet another embodiment of the present invention, multiplemechanical resonators can be attached together in a single sensor tomeasure a wider range of responses for a given fluid composition, asshown in FIGS. 17a, 17 b and 17 c. The multiple resonator sensor can befabricated from a single quartz piece such that all of the resonatorsare attached together by a common base, as shown in the figures. Themulti-resonator sensor could also be attached to multiple frequencygenerating circuits, such as multiple network analyzers 28, to measureproperties of the fluid compositions over multiple frequency sweeps sothat the generated data can be correlated to obtain additionalinformation about the liquid compositions. Because different resonatorstructures are best suited for measurement over different frequencyranges and for materials having different characteristics, a sensorcombining a plurality of different resonators can provide a morecomplete representation of the fluid composition's characteristics overa wider frequency range than a single resonator. FIGS. 17a, 17 b and 17c show specific examples of possible multi-resonator configurations, butthose of skill in the art would understand that sensors having anycombination of resonators can be constructed without departing from thescope of the invention.

[0145]FIG. 17a illustrates one possible sensor 100 configurationcontaining both a tuning fork resonator 102 and a TSM resonator 104.This type of sensor 100 can be used to, for example, measure themechanical and electrical properties of very thick liquids such aspolymer resins and epoxies. This sensor 100 can also be used to monitora material as it polymerizes and hardens. For example, the sensor 100can be placed in a liquid composition containing urethane rubber in itsdiluted state so that the tuning fork 102 is used initially to measureboth the composition's density viscosity product and its dielectricconstant. As the rubber changes to a gel and finally to a solid, thesensor 100 can switch to using the TSM resonator 104 to measure therubber's mechanical properties, leaving the tuning fork resonator 102 tooperate as a dielectric sensor only.

[0146] A sensor 106 for observing a fluid composition over a widefrequency range is shown in FIG. 10b. High polydispersity polymersolutions are ideally measured over a wide frequency spectrum, but mostresonators have optimum performance within a relatively limitedfrequency range. By combining different resonators having differentresonance frequencies and different response characteristics, it ispossible to obtain a more complete spectrum of resonator responses foranalyzing the fluid's characteristics under many different conditions.For example, due to the wide spectrum of polydisperse solutionrelaxation times, it is generally predicted that high molecular weightcompositions will react at lower frequencies than lighter molecularweight compositions. By changing the temperature, observing thefrequency response of different resonators, and correlating thedifferent resonator responses, it is possible to obtain a more accuratepicture of a composition's relaxation spectrum than from a singleresonator.

[0147] A low frequency tuning fork resonator 108 and a high frequencytuning fork resonator 110 in one sensor will probably suffice for mostwide-frequency range measurements. For certain cases, however, theresonators in the multi-resonator sensor 106 can also include a tridenttuning fork resonator 112, a length extension resonator 114, a torsionresonator 116, and a TSM resonator 118, membrane oscillators, bimorphs,unimorphs, and various surface acoustic wave devices, as well as anycombination thereof, or even a single resonator structure than canoperate in multiple mechanical modes (e.g. compression mode, axial mode,torsion mode). Of course, not all of these resonators are needed forevery application, but those of skill in the art can select differentcombinations that are applicable to the specific application in whichthe sensor 106 will be used.

[0148] Alternatively, multiple resonators having the same structure butdifferent coatings and/or functionalities can be incorporated into onesensor 120, as shown in FIG. 17c. In this example, a plurality of tuningfork resonators 122, 124, 126 have the same structure but have differentfunctionalities, each functionality designed to, for example, bond witha different target molecule. The high sensitivity of the tuning forkresonators 122, 124, 126 makes them particularly suitable for“artificial noses” that can detect the presence of anenvironmentally-offending molecule, such as hydrogen sulfide or nitrousoxide, in industrial emissions. When the sensor 120 is used in such anapplication, one tuning fork resonator 122 can, for example, befunctionalized with a material designed to bond with hydrogen sulfidewhile another resonator 124 can be functionalized with a materialdesigned to bond with nitrous oxide. The presence of either one of thesemolecules in the fluid composition being tested will cause thecorresponding tuning fork resonator 122, 124 to change its resonancefrequency, as explained with respect to FIGS. 16a and 16 b.

[0149] The tuning fork resonators 122, 124, 126 can also befunctionalized with a polymer layer or other selective absorbing layerto detect the presence of specific molecules in a vapor. Because thetuning fork resonators 122, 124, 126 are highly sensitive to thedielectric constant of the surrounding fluid, the tuning fork resonators122, 124, 126 can easily detect changes in the dielectric constant ofthe fluid and recognize a set of solvents with different dielectricconstants in the fluid. This information, combined with other observableparameters, makes tuning fork resonators particularly adaptable for usein artificial noses.

[0150] The method and system of the present invention has been describedabove in the combinatorial chemistry context, but it is not limited tosuch an application. Because the resonators in the method and system ofthe present invention have high sensitivities and quick response times,it can be also be used for in-line monitoring of fluid compositionsflowing through conduits or pipelines. For example, the invention can beused in a feedback system to monitor properties of liquids flowingthrough a gas or oil pipeline to monitor and control the concentrationof additives in the gas or oil, or to detect the presence of impuritiesin water flowing through a water pipe. The additives or impurities willchange the physical and electrical characteristics of the liquid flowingthrough the conduit. A functionalized tuning fork resonator 20 canfurther detect the presence of a specific chemical in a fluidcomposition, whether it is a liquid or a vapor, and can be used tomonitor the presence of, for example, a known chemical pollutant in asmokestack. The high sensitivity and quick response time of theresonator, and the tuning fork resonator 20 in particular, makes ituniquely suitable for such an application. The circuitry and system usedto generate the visual traces from the resonator's response can be thesame as described above or be any other equivalent resonator analysissystem.

[0151] Further, although the above description focuses primarily onusing TSM resonators and tuning fork resonators, any other mechanicalresonators exhibiting similar characteristics can be used. Tridents,cantilevers, torsion bars, bimorphs, and/or membrane resonators can besubstituted for the TSM resonator or tuning fork resonator withoutdeparting from the scope of the claimed invention.

[0152] It should be understood that various alternatives to theembodiments of the invention described herein may be employed inpracticing the invention. It is intended that the following claimsdefine the scope of the invention and that the methods and apparatuswithin the scope of these claims and their equivalents be coveredthereby.

[0153] It is understood that the above description is intended to beillustrative and not restrictive. Many embodiments as well as manyapplications besides the examples provided will be apparent to those ofskill in the art upon reading the above description. The scope of theinvention should, therefore, be determined not with reference to theabove description, but should instead be determined with reference tothe appended claims, along with the full scope of equivalents to whichsuch claims are entitled. The disclosures of all articles andreferences, including patent applications and publications, areincorporated by reference for all purposes.

We claim: 1: A method for in-line monitoring of a fluid composition, themethod comprising: placing a tuning fork resonator in contact with thefluid composition in a conduit; oscillating the resonator while thefluid composition is flowing the conduit; monitoring the resonator toobtain a resonator response; and determining at least two properties ofthe fluid composition based on the resonator response. 2: The method ofclaim 1, wherein the at least two properties are selected from the groupconsisting of viscosity, density, viscosity density product, molecularweight, specific weight, elasticity, dielectric constant, conductivity.3: The method of claim 2, wherein the at least two properties aresimultaneously determined based on the resonator response. 4: The methodof claim 2, wherein the at least two properties are separatelydetermined based on the resonator response. 5: The method of claim 2,wherein the at least two properties are viscosity and density. 6: Themethod of claim 2, wherein the at least two properties are viscosity anddielectric constant. 7: The method of claim 2, wherein the separatelydetermining step included separately determining at least threeproperties of the fluid composition. 8: The method of claim 7, whereinthe at least three properties are viscosity, dielectric constant andconductivity. 9: The method of claim 2, further comprising: calibratingthe resonator against a standard fluid or a number of standard fluidshaving known properties to obtain calibration data; and determining theat least two properties based on the calibration data and the resonatorresponse. 10: The method of claim 9, wherein the conduit is an oilpipeline. 11: A method for in-line monitoring of a fluid composition,the method comprising: calibrating a tuning fork resonator against astandard fluid or a number of standard fluids having known properties toobtain calibration data; placing the resonator in contact with the fluidcomposition in a conduit; oscillating the resonator while the fluidcomposition is flowing the conduit; monitoring the resonator to obtain aresonator response; and simultaneously determining at least twoproperties based on the calibration data and the resonator response. 12:The method of claim 11, wherein the at least two properties areviscosity and density. 13: The method of claim 11, wherein the at leasttwo properties are viscosity and dielectric constant.